Genotype–phenotype correlations in sepiapterin reductase deficiency. A splicing defect accounts for a new phenotypic variant

Sepiapterin reductase (SR) catalyzes the final step in the de novo synthesis of tetrahydrobiopterin, essential cofactor for phenylalanine, tyrosine, and tryptophan hydroxylases. SR deficiency is a very rare disease resulting in monoamine neurotransmitter depletion. Most patients present with clinical symptoms before the first year of age corresponding to a dopa-responsive dystonia phenotype with diurnal fluctuations, although some patients exhibit more complex motor and neurological phenotypes. Herein, we describe four new cases from Spain, their clinical phenotype and the biochemical and genetic analyses. Two mutations in the SPR gene were functionally expressed to provide a basis to establish genotype–phenotype correlations. Mutation c.751A>T is functionally null, correlating with the severe phenotype observed. The novel mutation c.304G>T was identified in three siblings with a strikingly mild phenotype without cognitive delay and close to asymptomatic in the eldest sister. Minigene analysis demonstrated that this mutation located in the last nucleotide of exon 1 affects splicing although some normal transcripts can be produced, resulting in the missense mutant p.G102C that retains partial activity. These results may account for the mild phenotype and the variable clinical presentations observed, which could depend on interindividual differences in relative abundance of correctly spliced and aberrant transcripts.